Maths.bangor.ac.uk

Antidepressants and suicide: risk–benefit conundrumsDavid Healy, MD; Chris Whitaker, MSc
Healy — Department of Psychological Medicine, University of Wales College of Medicine, Hergest Unit; Whitaker —School of Informatics, University of Wales Bangor, Bangor, United Kingdom.
There has been a long-standing controversy about the possibility that selective serotonin reuptakeinhibitor (SSRI) antidepressants might induce suicidality in some patients. To shed light on this issue, thispaper reviews available randomized controlled trials (RCTs), meta-analyses of clinical trials and epidem-iological studies that have been undertaken to investigate the issue further. The original clinical studiesraising concerns about SSRIs and suicide induction produced evidence of a dose-dependent link on a chal-lenge-dechallenge and rechallenge basis between SSRIs and both agitation and suicidality. Meta-analyses ofRCTs conducted around this time indicated that SSRIs may reduce suicidal ideation in some patients.These same RCTs, however, revealed an excess of suicidal acts on active treatments compared withplacebo, with an odds ratio of 2.4 (95% confidence interval 1.6–3.7). This excess of suicidal acts alsoappears in epidemiological studies. The data reviewed here make it difficult to sustain a null hypothesisthat SSRIs do not cause problems in some individuals. Further studies or further access to data are indi-cated to establish the magnitude of any risk and the characteristics of patients who may be most at risk.
La possibilité que les antidépresseurs inhibiteurs spécifiques du recaptage de la sérotonine (ISRS) entraînentdes tendances suicidaires chez certains patients soulève la controverse depuis longtemps. En vue d’éclairer laquestion, cette communication passe en revue les études contrôlées et randomisées (ECR), méta-analysesd’études cliniques et études épidémiologiques disponibles que l’on a effectuées pour l’approfondir. Lespremières études cliniques ayant soulevé des préoccupations au sujet des ISRS et des tendances suicidairesont produit des données probantes établissant un lien lié à la dose entre les ISRS et deux symptômes, l’agita-tion et les tendances suicidaires, suivant l’administration du médicament, la cessation, puis la reprise du traite-ment. Des méta-analyses des ECR réalisées à l’époque ont indiqué que les ISRS pourraient réduire les idéessuicidaires chez certains patients. Ces mêmes ECR ont néanmoins révélé des actes suicidaires en surnombredans le groupe de traitement actif, par rapport au placebo. À cet égard, le coefficient de probabilité s’est établià 2,4 (intervalle de confiance à 95 %, 1,6–3,7). Des études épidémiologiques ont aussi révélé des actessuicidaires en surnombre. Compte tenu des données examinées, il est difficile de soutenir l’hypothèse nullevoulant que les ISRS n’entraînent pas de problèmes chez certaines personnes. La réalisation de nouvellesétudes ou la diffusion d’autres données sont indiquées pour établir l’importance du risque et les caractéris-tiques des patients susceptibles d’être les plus vulnérables.Correspondence to: Dr. David Healy, Department of Psychological Medicine, University of Wales College of Medicine, Hergest Unit,Bangor, LL57 2PW United Kingdom; fax 44 1248 371397; Healy_Hergest@compuserve.com
Medical subject headings: antidepressive agents; epidemiology; meta-analysis; serotonin uptake inhibitors; suicide; treatment outcome.J Psychiatry Neurosci 2003;28(5):331-7.
Submitted Oct. 17, 2001Revised Apr. 4, 2003; May 30, 2003Accepted June 3, 2003
J Psychiatry Neurosci 2003;28(5)Introduction
analyzed the figures in terms of PEY only. Khan et al10found an excess of suicidal acts by individuals taking
The debate regarding selective serotonin reuptake
antidepressants compared with placebo, and this was
inhibitors (SSRIs) and suicide started in 1990, when
also replicated in another analysis,11 but the rates of sui-
Teicher, Glod and Cole1 described 6 cases in which
cidal acts in patients taking antidepressants and those
intense suicidal preoccupation emerged during fluox-
taking placebo were not significantly different in these
etine treatment. This paper was followed by others,2–6
analyses. Yet, another study12 reported that rates of sui-
which, combined, provided evidence of dose–response,
cidal acts of patients taking antidepressants for longer
challenge, dechallenge and rechallenge relations, as
durations may, in fact, fall relative to placebo, which
well as the emergence of an agreed mechanism by
might be expected because longer term studies will
which the effects were mediated and demonstrations
select patients suited to the agent being investigated.
that interventions in the process could ameliorate the
Although an analysis in terms of PEYs may be ap-
problems. A subsequent series of reports on the effects
propriate for an assessment of the risk of exposure to
of sertraline and paroxetine on suicidality and akathisia
placebo, it is inappropriate for the assessment of a
pointed to SSRI-induced suicidality being a class effect
problem that clinical studies had clearly linked to the
rather than something confined to fluoxetine.7
first weeks of active therapy. An analysis of suicidal
An induction of suicidality by SSRIs, therefore, had
acts on the basis of duration of exposure systematically
apparently been convincingly demonstrated according
selects patients who do not have the problem under in-
to conventional criteria for establishing cause and effect
vestigation, because those with the problem often drop
relations between drugs and adverse events, as laid out
out of the trial, whereas others who do well are kept on
by clinical trial methodologists, company investigators,
treatment for months or more on grounds of compas-
medico-legal authorities and the federal courts.8 Far less
consistent evidence led the Medicines Control Agency
The data presented by Khan and colleagues10 has
in Britain in 1988 to state unambiguously that benzodi-
accordingly been modified here in 4 respects (Table 1).
First, suicides and suicidal acts are presented in terms
Specifically designed randomized controlled trials
of absolute numbers of patients. Second, on the basis of
(RCTs) on depression-related suicidality at this time
an FDA paroxetine safety review13 and FDA statistical
would have established the rates at which this seem-
reviews on sertraline,14 it is clear that some of the sui-
ingly new phenomenon might be happening. How-
cides and suicidal acts categorized as occurring while
ever, no such studies have ever been undertaken. This
patients were taking placebo actually occurred during
review, therefore, will in lieu cover the RCT data on
a placebo washout period; placebo and washout sui-
newly released antidepressants and suicidal acts, the
cides are therefore distinguished here. Third, data for
meta-analyses of efficacy studies in depression that
citalopram, from another article by Khan et al,15 are in-
have been brought to bear on the question and relevant
cluded (although no details about the validity of as-
signments to placebo are available). Fourth, fluoxetinedata from public domain documents are presented,
Efficacy studies
again dividing the data into placebo and washoutperiod suicidal acts, along with data for venlafaxine.16
In lieu of specifically designed RCTs, the RCTs that
When washout and placebo data are separated and
formed the basis for the licence application for recent
analyzed in terms of suicidal acts per patient (ex-
antidepressants are one source of data. Khan and col-
cluding missing bupropion data) using an exact Man-
leagues10 recently analyzed RCT data to assess whether
tel–Haenszel procedure with a 1-tailed test for signifi-
it was ethical to continue using placebos in antidepres-
cance, the odds ratio of a suicide while taking these
sant trials. Although the US Food and Drug Adminis-
new antidepressants as a group compared with pla-
tration (FDA), in general, recommend that data from
cebo is 4.40 (95% confidence interval [CI] 1.32–infinity;
clinical trials be analyzed both in terms of absolute
p = 0.0125). The odds ratio for a suicidal act while tak-
numbers and patient exposure years (PEY), given that
ing these antidepressants compared with placebo is
an assessment of the hazards posed by placebo was the
2.39 (95% CI 1.66–infinity; p ≤ 0.0001). The odds ratio
object of this study, the investigators appropriately
for a completed suicide while taking an SSRI antide-
Rev Psychiatr Neurosci 2003;28(5)
pressant (including venlafaxine) compared with
mixture of trials. The current analysis limits the num-
placebo is 2.46 (95% CI 0.71–infinity; p = 0.16), and the
ber of studies but ensures that they are roughly com-
odds ratio for a suicidal act while taking SSRIs com-
parable, and the selection of studies is based on regula-
pared with placebo is 2.22 (95% CI 1.47–infinity; p ≤
tory requirements rather than individual bias.
If washout suicidal acts are included with placebo, as
Meta- and other analyses of SSRIs
the companies appear to have done, but adjusting the
and suicidal acts
denominator appropriately, the relative risk of suicidalacts while taking sertraline, paroxetine or fluoxetine
In addition to the RCT data indicating an excess of sui-
compared with placebo becomes significant, with fig-
cidal acts by those taking SSRIs, the clinical trials on
ures ranging from 3.0 for sertraline to over 10.0 for flu-
zimelidine, the first SSRI, suggested there were more
suicide attempts by patients taking it than by those
Other data sets yield similar findings. For instance, in
taking comparators, but Montgomery and colleagues18
Pierre Fabre’s clinical trial database of approximately
reported that although this might be the case, zimeli-
8000 patients, the rate for suicidal acts by those taking
dine appeared to do better than comparators in reduc-
SSRIs appears to be 3 times the rate for other antide-
ing already existing suicidal thoughts. A similar analy-
pressants.17 However, these other data sets include a
sis demonstrated lower suicide attempt rates for thosetaking fluvoxamine than the comparators in clinicaltrials.19 Problems with paroxetine led to similar analy-
Table 1: Incidence of suicides and suicide attempts inantidepressant trials from Khan et al10,15 and Kirsch et al16
The best-known analysis of this type was published
by Eli Lilly after the controversy with fluoxetine
emerged; from the analysis of pooled data from 17
double-blind clinical trials in patients with major
depressive disorder, the authors concluded that “data
from these trials do not show that fluoxetine is asso-
ciated with an increased risk of suicidal acts or emer-
gence of substantial suicidal thoughts among
depressed patients.”22 There are a number of method-
ological problems with Lilly’s analysis, however, and
these apply to some extent to all other such exercises.
First, none of the studies in the analysis were designed
to test whether fluoxetine could be associated with the
emergence of suicidality. In the case of fluoxetine, all of
the studies had been conducted before concerns of sui-
cide induction had arisen. Some of the studies used in
the analysis had, in fact, been rejected by the FDA.
Second, only 3067 patients of the approximately 26 000
patients entered into clinical trials of fluoxetine were
included in this meta-analysis. Third, no mention was
made of the fact that benzodiazepines had been co-
prescribed in the clinical trial program to minimize the
agitation that Lilly recognized fluoxetine could cause.8
All investigational drugs
Fourth, no reference was made to the 5% of patients
All SSRIs*
who dropped out because of anxiety and agitation.
Given that this was arguably the very problem that
was at the heart of the issue, the handling of this issue
was not reassuring. The 5% dropout rate for agitation
*SSRI = selective serotonin reuptake inhibitor.
or akathisia holds true for other SSRIs as well, and the
J Psychiatry Neurosci 2003;28(5)
differences between SSRIs and placebo are statistically
suicidality. In a fourth study of 643 patients, conceived
significant. Given that the Diagnostic and Statistical
20 years before fluoxetine was launched and instituted
Manual of Mental Disorders, fourth edition, text revision
10 years before launch, only 185 patients received flu-
(DSM-IV-TR) has connected akathisia with suicide risk,
oxetine at any point.29 This was clearly not a study
designed to establish whether fluoxetine might induce
Finally, this and other analyses depend critically on
suicidality. None of these studies fit the definition of
item 3 (i.e., suicide) of the Hamilton Rating Scale for
Depression; this approach to the problem is one that
Although not properly epidemiological, 2 post-
FDA officials, Lilly personnel and Lilly’s consultants8
marketing surveillance studies that compared SSRI
agreed was methodologically unsatisfactory. The argu-
with non-SSRI antidepressants found a higher rate of
ment in these meta-analyses has, broadly speaking,
induction of suicidal ideation for those taking SSRIs,
been that in the randomized trials, the SSRI reduced
although not in the rates of suicidal acts or suicides.30,31
suicidality on item 3 and that there was no emergence
In a more standard epidemiological study of 222 sui-
of suicidality, as measured by this item. To claim that
cides, Donovan et al32 reported that 41 of those suicides
the prevention of or reduction of suicidality in some
were committed by people who had been taking an
patients in some way means that treatment cannot pro-
antidepressant in the month before their suicide; there
duce suicidality in others is a logical non sequitur. The
was a statistically significant doubling of the relative
argument that item 3 would pick up emergent suicidal-
risk of suicide in those taking SSRIs compared with tri-
ity in studies run by clinicians who are not aware of this
cyclic antidepressants. In a further epidemiological
possible adverse effect has no evidence to support it.
study of 2776 acts of deliberate self-harm, Donovan et
Despite these methodological caveats, the claim that
al33 found a doubling of the risk for deliberate self-
SSRIs reduce suicidality in some patients appears
harm for those taking SSRIs compared with other anti-
strong. However, insofar as SSRIs reduce suicidal acts
in some, if there is a net increase in suicidal acts asso-
A set of post-marketing surveillance studies carried
ciated with SSRI treatment in these same trials, the
out in primary care in the United Kingdom by the Drug
extent to which SSRIs cause problems for some pa-
Safety Research Unit (DSRU)34 recorded 110 suicides in
tients must be greater than is apparent from consider-
over 50 000 patients being treated by general practition-
ers in Britain. The DSRU methodology has since beenapplied to mirtazapine, where there have been 13 sui-
Epidemiological studies
cides reported in a population of 13 554 patients.35 Thispermits the comparisons outlined in Table 2.
Epidemiology traditionally involves the study of repre-
A further study from British primary care was un-
sentative samples of the population and requires a
dertaken by Jick and colleagues,36 who investigated the
specification of the methods used to make the sample
rate and means of suicide among people taking com-
representative. A series of what have been termed epi-
mon antidepressants. They reported 143 suicides
demiological studies have been appealed to in this
among 172 580 patients taking antidepressants and
debate. The first is a 1-column letter involving no sui-
found a statistically significant doubling of the relative
cides.24 The second is a selective retrospective post-marketing chart review25 involving no suicides, which
Table 2: Drug Safety Research Unit studies of selective
analyzed by the American College of Neuropsy-
serotonin reuptake inhibitors (SSRIs) and mirtazapine in
chopharmacology, the FDA and others,26,27 shows a 3-
primary care practice in the United Kingdom
fold increased relative risk of emergent suicidality for
fluoxetine versus other antidepressants.
A third study was conducted by Warshaw and
Keller28 on patients with anxiety disorder, in which the
only suicide was committed by a patient taking fluoxe-
tine. However, only 192 of the 654 patients in this
Total SSRIs
study received fluoxetine. This, therefore, was not a
study designed to test fluoxetine’s capacity to induce
Rev Psychiatr Neurosci 2003;28(5)
risk of suicide with fluoxetine compared with the refer-
100 000 patients in non-hospitalized depression. An-
ence antidepressant, dothiepin, when calculated in
other primary care study from the Netherlands gives a
terms of patient exposure years. Controlling for con-
suicide rate of 33 per 100 000 patient years.38 Finally, Si-
founding factors such as age, sex and previous suicide
mon and VonKorff39 in a study of suicide mortality
attempts left the relative risk at 2.1 times greater for
among individuals treated for depression in Puget
fluoxetine than for dothiepin and greater than any
Sound, Wash., reported 36 suicides in 62 159 patient
other antidepressant studied, although statistical
years. The suicide risk per 100 000 patient years was 64
significance was lost in the process. Of further note are
among those who received outpatient specialty mental
the elevated figures for mianserin and trazodone,
health treatment, 43 among those treated with antide-
which are closely related pharmacologically to mirtaza-
pressant medications in primary care and 0 among
pine and nefazodone. Controlling for confounding
those treated in primary care without antidepressants.
factors in the case of mianserin and trazodone, how-
Utilizing a database of 2.5 million person years and
ever, led to a reduction in the relative risk of these
212 suicides from North Staffordshire, Boardman and
Healy40 modelled the rate for suicide in treated or un-
To provide comparability with other figures, I have
treated depression and found it to be of the order of
recalculated these data in terms of absolute numbers
68/100 000 patient years for all affective disorders.40
and separated the data for fluoxetine (Table 3). The
This rate gives an upper limit on the suicide rate in
data in the Jick study, however, only allow compar-
mood disorders that is compatible with observed
isons between antidepressants.36 They shed no light on
national rates of suicide in the United Kingdom. Board-
the differences between treatment with antidepressants
man and Healy estimate a rate of 27 suicides per
and non-treatment or on the efficacy of antidepressants
100 000 patients per annum for primary care primary
in reducing suicide risk in primary care. The traditional
affective disorders. Possible relative risks for SSRIs
figures with which the DSRU studies and the Jick
from the DSRU studies set against these figures and
study might be compared are a 15% lifetime risk for
the findings from the Jick study for all antidepressants
suicide for affective disorders. This would be inappro-
excluding fluoxetine are presented in Table 4.
priate, however, because this 15% figure was derived
Comparing the figures for SSRIs from Table 2 with
from patients with melancholic depression in hospital
those for the non-SSRI antidepressants from the Jick
study gives a mean figure for non-SSRI antidepressants
There are very few empirical figures available for
of 68 suicides per 100 000 patients exposed compared
suicide rates in primary care depression, the sample
with a figure of 212 suicides for the SSRI group. Based
from which the Jick et al36 and DSRU34 data come. One
on an analysis of 249 803 exposures to antidepressants,
study from Sweden37 reports a suicide rate of 0 per
therefore, the broad relative risk on SSRI antidepres-sants compared with non-SSRI antidepressants or evennon-treatment is 234/68 or 3.44.Table 3: Suicides rates of patients taking antidepressants inprimary care settings in the United Kingdom*
There are 2 points of note. First, these low rates for
suicide in untreated primary care mood disorder pop-
Table 4: Relative risk (RR) of suicide while taking SSRIs (fromDSRU studies) compared with general risk of suicide in UKprimary care primary affective disorders40 and in UK primarycare depression treated with non-SSRI antidepressants36Total SSRI
Note: CI = confidence interval.*From Jick et al.36
Note: DSRU = Drug Safety Research Unit.J Psychiatry Neurosci 2003;28(5)
ulations are consistent with the rate of 0 suicides in
in children and adolescents during fluoxetine treatment. J Am
those taking placebo in antidepressant RCTs. Second,
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Conclusion
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Since antidepressant drug treatments were intro-
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Canadian College of NeuropsychopharmacologyCollège canadien de neuropsychopharmacologieW.G. Dewhurst Travel Awards
The CCNP is making available up to 6 travel awards for research trainees who would not otherwise beable to attend the Annual Meeting (to be held in 2004 in Kingston, Ont.). The awards are for the leastexpensive airfare available (to be approved by the CCNP Treasurer) plus $250. Research trainees (gradu-ate students, postdoctoral fellows or clinical residents) working in Canada or Canadian research traineesworking abroad are eligible to receive the bursaries. Travel bursaries will be awarded to those whosubmit the best abstracts.
Those who wish to apply should send a completed abstract form with a letter of support from their researchsupervisor to:
Ms. Rachelle Anderson, 1E7.19, Department of Psychiatry,
University of Alberta, 8440-112 St., Edmonton AB T6G 2B7;
Deadline: April 2, 2004. Applicants will be notified by April 19 of the decision of the Committee.J Psychiatry Neurosci 2003;28(5)

FRUIT AND FOOD TECHNOLOGY RESEARCH INSTITUTE, STELLENBOSCH INDIGENOUS FLOWERS – CIRCULAR No. 2 – OCTOBER, 1965 WHERE CAN PROTEAS BE CULTIVATED? Most South African Proteaceae show a remarkable adaptability with regard to climatic conditions and can be cultivated in both summer and winter rainfall areas. Yet their growth is influenced by various factors which must be taken into consider

Gastric Ulcers: Your Questions Answered Since the first Gastric Ulcer Awareness Month in 2007, it has been well documented that approximately 60 per cent of performance horses are affected by gastric ulcers. Despite this, it is believed that it is still one of the most under-recognised problems in the equine The main reason for this lack of detection is likely to be the vague and non-spec